ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.1616C>T (p.Pro539Leu) (rs179363889)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000059052 SCV000329058 pathogenic not provided 2017-12-21 criteria provided, single submitter clinical testing The P539L missense variant in the AIRE gene has been reported previously in association with APECED (Meloni et al., 2002; Mazza et al., 2011), and has been seen in the homozygous state in multiple affected individuals at GeneDx. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. P539L is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Counsyl RCV000409203 SCV000485843 likely pathogenic Polyglandular autoimmune syndrome, type 1 2016-02-25 criteria provided, single submitter clinical testing
Invitae RCV000409203 SCV000827161 likely pathogenic Polyglandular autoimmune syndrome, type 1 2018-02-23 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 539 of the AIRE protein (p.Pro539Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs179363889, ExAC 0.009%). This variant has been reported in several homozygous and compound heterozygous individuals affected with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (PMID: 11836330, 28446514, 17289071, 21295522, 15811934). ClinVar contains an entry for this variant (Variation ID: 68218). Experimental studies have shown that this missense change causes severely reduced transactivation activity of the AIRE protein (PMID: 17675238). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Blueprint Genetics RCV000059052 SCV000927331 pathogenic not provided 2017-07-10 criteria provided, single submitter clinical testing
UniProtKB/Swiss-Prot RCV000059052 SCV000090573 not provided not provided no assertion provided not provided

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